BBS is an autosomal recessive disorder characterized by retinal degeneration, obesity, polydactyly, mental retardation, renal anomalies, and hypogonadism. In addition, BBS is associated with an increased incidence of diabetes mellitus, hypertension and congenital heart disease. Over the past few years, we and others have demonstrated that the disorder is genetically heterogeneous and is caused by at least six independent loci. Recently, we have identified three of the genes causing this disorder, and have also narrowed the genetic interval for other BBS loci. The primary objective of this application is to identify additional genes causing this syndrome. We propose to discover additional BBS genes by the positional cloning of BBS1 (chromosome 11) and BBS3 (chromosome 3), and by the evaluation of candidate genes for BBS5 (chromosome 2). Furthermore, we will characterize the recently discovered BBS2, BBS4 and MKKS (BBS6) genes and their protein products by the identification of additional human mutations in each gene; by the determination of the pattern of gene expression; by determination of the intracellular location of the protein product; and by identification of potential interactions among these proteins, as well as interactions with other proteins. We also plan to develop and characterize knockout mouse models for BBS2 and BBS4. Accomplishment of these aims will add to the understanding of disease mechanisms involved in human retinal degeneration, as well as provide insight into a number of other common human disorders.